Muscarinic acetylcholine receptors play a central role in the central nervous system for higher cognitive functions, as well as in the peripheral parasympathetic nervous system. Cloning has established the presence of five distinct muscarinic receptor subtypes (termed m1-m5) (cf. T. I. Bonner et al, Science 237, 1987, pp. 527-532; T. I. Bonner et al., Neuron 1, 1988, pp. 403-410). It has been found that m1 is the predominant subtype in the cerebral cortex and is believed to be involved in the control of cognitive functions, m2 is predominant in heart and is believed to be involved in the control of heart rate, m3 is believed to be involved in gastrointestinal and urinary tract stimulation as well as sweating and salivation, m4 is present in brain, and m5 is present in brain and may be involved certain functions of the central nervous system associated with the dopaminergic system.
Animal studies of various muscarinic ligands (S. Iversen, Life Sciences 60 (Nos. 13/14), 1997, pp. 1145-1152) have shown that muscarinic compounds have a profound effect on cognitive functions, e.g. learning and memory. This would suggest a potential utility of muscarinic agonists in the improvement of cognitive functions in diseases characterized by cognitive impairment, both age-related (such as Alzheimer's disease or other dementias) and not age-related (such as attention deficit hyperactivity disorder). Based on the presence of muscarinic receptor subtypes in various tissues, it would appear that the m1 receptor subtype is the more abundant one in the cerebral cortex, basal ganglia and hippocampus where it accounts for 35-60% of all muscarinic receptor binding sites (cf. A. Levey, Proc. Natl. Acad. Sci. USA 93, 1996, pp. 13541-13546). It has been proposed that the m1 (and possibly m4) subtype plays a major role as a postsynaptic muscarinic receptor (located on cholinoceptive neurons in the neocortex and hippocampus) in various cognitive and motor functions and is likely to be a major contributor to the m 1 responses measured in these regions of the brain.
It has previously been found that conditions associated with cognitive impairment, such as Alzheimer's disease, are accompanied by selective loss of acetylcholine in the brain. This is believed to be the result of degeneration of cholinergic neurons in the basal forebrain which innervate areas of the association cortex and hippocampus involved in higher processes (cf S. Iversen, supra). This finding would suggest that such conditions may be treated or at least ameliorated with drugs that augment the cholinergic function in the affected areas of the brain.
Treatment with acetylcholine esterase (AChE) inhibitors such as 9-amino-1,2,3,4-tetrahydroacridine (tacrine) results in an increase of acetylcholine in the brain which indirectly causes stimulation of muscarinic receptors. Tacrine treatment has resulted in a moderate and temporary cognitive improvement in Alzheimer's patients (cf. Kasa et al., supra). On the other hand, tacrine has been found to have cholinergic side effects due to the peripheral acetylcholine stimulation. These include abdominal cramps, nausea, vomiting, diarrhea, anorexia, weight loss, myopathy and depression. Gastrointestinal side effects have been observed in about a third of the patients treated. Tacrine has also been found to cause significant hepatotoxicity, elevated liver transaminases having been observed in about 30% of the patients (cf. P. Taylor, “Anticholinergic Agents”, Chapter 8 in Goodman and Gilman: The Pharmacological Basis of Therapeutics, 9th Ed., 1996, pp. 161-176). The adverse effects of tacrine have severely limited its clinical utility. Another AChE inhibitor, (R,S)-1-benzyl-4-[5,6-dimethoxy-1-indanon-2yl]methylpiperidine.HCl (donepezil), has recently been approved for the treatment of symptoms of mild to moderate Alzheimer's disease (cf. P. Kasa et al, supra). No hepatic damage has been observed for this compound but it has gastrointestinal effects similar to those of tacrine, probably due to stimulation of the m3 receptor caused by elevated parasympathetic tone.
It has previously been suggested that, since the muscarinic m1 receptors in the prefrontal cortex and hippocampus appear to be intact, it may be possible to remedy or at least ameliorate the loss of acetylcholine in Alzheimer's disease patients by administration of drugs acting as agonists on those muscarinic receptors (cf. J. H. Brown and P. Taylor, “Muscarinic Receptor Agonists and Antagonists”, Chapter 7 in Goodman and Gilman: The Pharmacological Basis of Therapeutics, 9th Ed., 1996, p. 147).
The muscarinic agonists (believed to be m1 selective) hitherto suggested for the treatment of Alzheimer's disease, such as arecoline, have not shown greater efficacy in clinical trials than AChE inhibitors (cf. S. V. P. Jones et al., supra). In one study (cf. T. Sunderland et al., Brain Res. Rev. 13, 1988, pp. 371-389), arecoline was found to have not so much cognitive enhancing effects as effects on behavioral changes often observed in Alzheimer's disease patients, such as a significant increase in motor activity, significant uplifting of mood, and significant decrease in anergia. However, presumed m1 agonists have later been found to be weak partial agonists selective for the m2 and/or m3 receptor subtypes (H. Bräuner-Osbome et al., J. Med. Chem. 38, 1995, pp. 2188-2195). As indicated above, m2 subtype selectivity is presumed to be responsible for the cardiovascular effects observed for these agonists, e.g. tachycardia and bradycardia, and m3 activity is believed to account for the adverse gastrointestinal effects of the agonists.
m2 and/or m3 activity is therefore a significant drawback for the muscarinic agonists proposed until now for the treatment of Alzheimer's disease, severely limiting the doses of the drugs which it has been possible to administer to patients who may therefore have received sub-optimal doses. Furthermore, the lack of subtype selectivity and low potency of the currently tested cholinergic compounds appear to favor the negative peripheral side effects and have limited cognitive effects because of weak and/or opposing actions in the brain. It would therefore be of great advantage to develop compounds which have an improved selectivity for the m1 subtype, but which have little or no activity on the m2 and m3 subtypes.